Method For Preparing Formamidines

ABSTRACT

A method for preparing formamidines of formula (I) in a single step by reducing ureas of formula (II) using silanes of formula (III), according to reaction (II)+(III)+(I) is provided. The present invention also provides a method for preparing insecticides, pesticides, fungicides, pharmaceutical products and catalysts, including a step of preparing formamidines of formula (I) according to the invention.

The present invention relates to a process for the preparation, in asingle stage, of formamidines by catalytic hydrosilylation of organicureas.

Formamidines are basic molecules in the chemical industry. They are usedin various industries and in particular for their applications as:

-   -   insecticides, pesticides, fungicides (J. Agric. Food Chem.,        1977, Vol. 25, No. 3, 493-501; Ecotoxicology and Environmental        Safety, 1996, 33, 163-167; J. Agric. Food Chem., 1969, Vol. 17,        No. 3, 595-600; Bull. Environ. Contam. Toxicol., 2000, 65,        22-27),    -   pharmaceutical active principles (Clin. Pharmacol. Ther., 1999,        65, 369-376; Eur. J. Pharmacol., 1994, 288, 17-25),    -   synthesis reactants (Chem. Rev., 2011, 111, 2705-2733; Org.        Lett., 2009, Vol. 11, No. 4, 1019-1022),    -   ligand for the preparation of catalysts (Eur. J. Org. Chem.,        2010, 4893-4901).

Thus, the present invention also relates to a process for themanufacture of insecticides, pesticides, fungicides, pharmaceuticalproducts and catalysts comprising a stage of preparation of formamidinesaccording to the process of the invention. Formamidines can also be usedas intermediates in the synthesis of N-heterocyclic carbenes (Chem.Rev., 2011, 111, 2705-2733; Org. Lett., 2009, Vol. 11, No. 4,1019-1022), or in the synthesis of alkaloids used in therapeuticchemistry (J. Org. Chem., 1996, 61, 573-580).

The synthesis of formamidines by reduction of organic ureas (also knownas ureas) is an attractive synthesis route as ureas are stable andrelatively nontoxic compounds which can be prepared in a simple way fromcarbon dioxide CO₂ (Angew. Chem. Int. Ed., 2003, 42, 3257-3260; GreenChem., 2010, 12, 1811-1816).

However, the carbonyl functional groups of ureas are very difficult toreduce due to their thermodynamic stability (Angew. Chem. Int. Ed.,2011, 50, 11702-11705). Their reduction requires the use of powerfulreducing agents, such as lithium aluminum hydride (LiAlH₄) (J. Org.Chem., 1964, 29, 3697-3700; J. Org. Chem., 1950, 15, 1020-1022) orsodium borohydride (NaBH₄) (Tetrahedron Lett., 1969, No. 9, 699-702),which exhibit the disadvantage of also reducing other functional groupswhich may be present.

The use of mild reducing agents, such as hydrogen, has ended in failure.This is because the urea is directly reduced to amines and methanol andthe formamidine compound as such cannot be isolated (Angew. Chem. Int.Ed., 2011, 50, 11702-11705).

The inventors have discovered that the silanes corresponding to thefollowing formula

are attractive reducing agents for the reduction of ureas to giveformamidines insofar as they are not very reactive, tolerated byfunctional groups (other than the carbonyl functional groups of theureas), available commercially, stable and not very toxic (J. Chem.Soc., Perkin Trans. 1, 1999, 3381-3391).

Thus, the present invention relates to a process for the synthesis offormamidines of formula (I) by reduction of ureas of formula (II) bysilanes of formula (In), according to the following reaction:

Conventionally, formamidines of general formula (I) are synthesized bycondensation of a formamide of formula R¹R²NCOH with an amine of formulaR³NH₂ in the presence of a strong dehydrating agent, such as thionylchloride (SOCl₂) (J. Med. Chem., 1988, 31, 1816-1820), phosphoryltrichloride (POCl₃) (Eur. J. Org. Chem., 2010, 4893-4901; Bioorg. Med.Chem. Lett., 2010, 20, 6781-6784) or trifluoroacetic anhydride(Tetrahedron, 2006, 62, 5617-5625). These synthesis routes generallyrequire moderate to strong heating which can range up to 180° C. andinvolve the handling of toxic reactants (SOCl₂, POCl₃, and the like).

An alternative route consists of the synthesis of formamidines byreaction between a primary amine and a trialkyl orthoformate, forexample (EtO)₃CH or (MeO)₃CH (Org. Lett., 2009, Vol. 11, No. 4,1019-1022; Synlett., 2011, No. 3, 405-409; J. Am. Chem. Soc., 1954, 76,3978-3982).

Formamidines can also be obtained by reduction of the correspondingureas. This method may appear attractive insofar as ureas can be easilyprepared by condensation of amines with carbon dioxide CO₂, which aremolecules which are stable and easy to store. The synthesis offormamidines then requires the use of powerful reducing agents, such asLiAlH₄, NaBH₄, triethyl orthoformate ((EtO)₃CH) (J. Am. Chem. Soc.,1955, 77, 5872-5877) or a dimethylaminoborane/trichlorophosphate mixture(Synthesis-Stuttgart, 1986, No. 3, 226-228). The methods described inthe state of the art thus require the use of reactants which are toxic(POCl₃) or unstable with regard to water (LiAlH₄, NaBH₄, (EtO)₃CH) andconsequently difficult to store. Furthermore, they are not veryselective and are incompatible with the presence of functional groups.

There thus exists a real need for a process for the preparation offormamidines which overcomes the disadvantages of the prior art andwhich makes it possible to obtain, in a single stage with a good yieldand an excellent selectivity, formamidines by reduction of ureas bysilanes, while not reducing the other functional groups which may bepresent on the urea.

The inventors have succeeded in developing a process for the synthesisof formamidines in a single stage via a unique reaction unknown to date.

The synthesis process for the present invention combines the followingadvantages over the existing systems:

-   -   the use of organic ureas as starting material, and    -   the use of hydrosilanes as reducing agents, the latter being        known to be stable, not very toxic and tolerated by numerous        functional groups.

Thus, a first subject matter of the invention is a process for thepreparation of formamidines of formula (I):

in which:

-   -   R¹, R² and R³ represent, independently of one another, a        hydrogen atom, an alkyl, alkenyl, alkynyl, aryl or heteroaryl        group, a heterocycle or a silyl, siloxy or amino group, said        alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, silyl,        siloxy and amino groups optionally being substituted, or    -   R¹ and R², taken together with the nitrogen atom to which they        are bonded, form an optionally substituted heterocycle, or    -   R¹ and R³, taken together with the nitrogen atom to which they        are bonded, form an optionally substituted heterocycle,        characterized in that a urea of formula (II), in which R′, R²        and R³ are as defined above:

is reacted, in the presence of a catalyst, with a silane compound offormula (III):

in which n is an integer varying from 1 to 20 000, and

-   -   when n=1 and Y represents a single bond, and        -   R⁴, R⁵ and R⁶ represent, independently of one another, a            hydrogen or halogen atom, a hydroxyl, alkyl, alkenyl,            alkynyl, aryl or alkoxy group or a silyl, siloxy or amino            group, said alkyl, alkenyl, alkynyl, aryl, alkoxy, silyl,            siloxy and amino groups optionally being substituted, or        -   R⁶ is as defined above and R⁴ and R⁵, taken together with            the silicon atom to which they are bonded, form an            optionally substituted silylated heterocycle, or    -   when n>1, Y is an oxygen atom, and        -   R⁴ represents a hydrogen or a halogen atom or an alkyl or            alkoxy group,        -   R⁵ represents a silyl group of formula —Si(X)₃ in which each            X group, independently of one another, is chosen from a            hydrogen or halogen atom or an alkyl or alkoxy group,        -   R⁶ represents a siloxy group of formula —O—Si(X)₃ in which            each X group, independently of one another, is chosen from a            hydrogen or halogen atom, or an alkyl or alkoxy group.

The process of the invention has the advantage of making possible thesynthesis of formamidines with a good yield (of the order of 30% to100%) and a very good selectivity.

In the context of the present invention, the yield is calculated withrespect to the amount of urea of formula (II) initially introduced, onthe basis of the amount of formamidine of formula (I) isolated:

Yield=n(urea)/(n(urea)+n(formamidine)),

n being the amount of material.

In the context of the present invention, the selectivity refers to thenature of the products formed from the urea of formula (II).

Within the meaning of the present invention, “alkyl” is understood tomean an optionally substituted, linear, branched or cyclic and saturatedor unsaturated carbon-based radical comprising from 1 to 12 carbonatoms. Mention may be made, as saturated and linear or branched alkyl,for example, of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,octyl, nonyl, decyl, undecyl and dodecanyl radicals and their branchedisomers. Mention may be made, as cyclic alkyl, of the cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.1.1]hexyl andbicyclo[2.2.1]heptyl radicals. Mention may be made, as unsaturatedcyclic alkyls, for example, of cyclopentenyl and cyclohexenyl. Theunsaturated alkyls also known as “alkenyl” or “alkynyl” respectivelycomprise at least one double or one triple bond. Mention may be made, assuch, for example, of the ethylenyl, propylenyl, butenyl, pentenyl,hexenyl, acetylenyl, propynyl, butynyl, pentynyl and hexynyl radicalsand their branched isomers. The alkyl group, within the meaning of theinvention including the alkenyl and alkynyl groups, can optionally besubstituted by one or more hydroxyl groups, one or more alkoxy groups,one or more halogen atoms chosen from fluorine, chlorine, bromine andiodine atoms, one or more nitro (—NO₂) groups, one or more nitrile (—CN)groups, or one or more aryl groups, with the alkoxy and aryl groups asdefined in the context of the present invention.

The term “aryl” denotes generally a cyclic aromatic substituentcomprising from 6 to 20 carbon atoms. In the context of the invention,the aryl group can be mono- or polycyclic. Mention may be made, by wayof indication, of the phenyl, benzyl and naphthyl groups. The aryl groupcan optionally be substituted by one or more hydroxyl groups, one ormore alkoxy groups, one or more halogen atoms chosen from fluorine,chlorine, bromine and iodine atoms, one or more nitro (—NO₂) groups, oneor more nitrile (—CN) groups, one or more alkyl groups or one or morearyl groups, with the alkoxy, alkyl and aryl groups as defined in thecontext of the present invention.

The term “heteroaryl” denotes generally a mono- or polycyclic aromaticsubstituent comprising from 5 to 10 members, including at least 2 carbonatoms and at least one heteroatom chosen from nitrogen, oxygen orsulfur. The heteroaryl group can be mono- or polycyclic. Mention may bemade, by way of indication, of the furyl, benzofuranyl, pyrrolyl,indolyl, isoindolyl, azaindolyl, thiophenyl, benzothiophenyl, pyridyl,quinolinyl, isoquinolyl, imidazolyl, benzimidazolyl, pyrazolyl,oxazolyl, isoxazolyl, benzoxazolyl, thiazolyl, benzothiazolyl,isothiazolyl, pyridazinyl, pyrimidilyl, pyrazinyl, triazinyl,cinnolinyl, phthalazinyl and quinazolinyl groups. The heteroaryl groupcan optionally be substituted by one or more hydroxyl groups, one ormore alkoxy groups, one or more halogen atoms chosen from fluorine,chlorine, bromine and iodine atoms, one or more nitro (—NO₂) groups, oneor more nitrile (—CN) groups, one or more aryl groups or one or morealkyl groups, with the alkyl, alkoxy and aryl groups as defined in thecontext of the present invention.

The term “alkoxy” means an alkyl group, as defined above, bonded via anoxygen atom (—O-alkyl).

The term “heterocycle” denotes a saturated or unsaturated and mono- orpolycyclic substituent comprising from 5 to 10 members and comprisingfrom 1 to 4 heteroatoms chosen, independently of one another, fromnitrogen, oxygen and sulfur. Mention may be made, by way of indication,of the morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl,imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl,tetrahydropyranyl, thianyl, oxazolidinyl, isoxazolidinyl, thiazolidinyland isothiazolidinyl substituents. The heterocycle can optionally besubstituted by one or more hydroxyl groups, one or more alkoxy groups,one or more aryl groups, one or more halogen atoms chosen from fluorine,chlorine, bromine and iodine atoms, one or more nitro (—NO₂) groups, oneor more nitrile (—CN) groups or one or more alkyl groups, with thealkyl, alkoxy and aryl groups as defined in the context of the presentinvention.

Halogen atom is understood to mean an atom chosen from fluorine,chlorine, bromine or iodine atoms.

“Silyl” group is understood to mean a group of formula —Si(X)₃ in whicheach X group, independently of one another, is chosen from a hydrogenatom, one or more halogen atoms chosen from fluorine, chlorine, bromineor iodine atoms, one or more alkyl groups, one or more aryl groups orone or more alkoxy groups, with the alkyl, aryl and alkoxy groups asdefined in the context of the present invention.

“Siloxy” group is understood to mean a silyl group, as defined above,bonded via an oxygen atom (—O—Si(X)₃).

Within the meaning of the invention, “silylated heterocycle” isunderstood to mean a saturated or unsaturated and mono- or polycyclicsubstituent comprising from 5 to 15 members and comprising at least onesilicon atom and optionally at least one other heteroatom chosen fromnitrogen, oxygen or sulfur. Said silylated heterocycle can optionally besubstituted by one or more hydroxyl groups, one or more alkyl groups,one or more alkoxy groups, one or more halogen atoms chosen fromfluorine, chlorine, bromine and iodine atoms or one or more aryl groups,with the alkyl, alkoxy and aryl groups as defined in the context of thepresent invention. Mention may be made, among silylated heterocycles,for example, of 1-silacyclo-3-pentene or1-methyl-1-hydrido-2,3,4,5-tetraphenyl-1-silacyclopentadiene,corresponding to the formulae below:

Mention may also be made, for example, of methylsiloxane,1-phenyl-1-silacyclohexane, 1-silabicyclo[2.2.1]heptane,1-methyl-1-silacyclopentane and 9,9-dihydro-9-silafluorene,corresponding to the formulae below:

The silylated heterocycles of the invention can be availablecommercially or can, if appropriate, be prepared by known synthesisprocesses, such as, for example, those described by C. L. Smith et al.,J. Org. Chem., 1974, 81, 33-40; G. D. Homer, J. Am. Chem. Soc., 1973,95:23, 7700-7707; L. Spialter et al., J. Am. Chem. Soc., 1971, 93:22,5682-5686; R. West, J. Am. Chem. Soc., 1954, 76, 6015-6017. A personskilled in the art is in a position to employ and adapt the knownprocesses to the synthesis of the various silylated heterocycles whichhe needs.

“Amino” group is understood to mean a group of formula —NR⁷R⁸ in which:

-   -   R⁷ and R⁸ represent, independently of one another, a hydrogen        atom, an alkyl, alkenyl, alkynyl, aryl or heteroaryl group, a        heterocycle or a silyl or siloxy group, with the alkyl, alkenyl,        alkynyl, aryl, heteroaryl, heterocycle, silyl and siloxy groups        as defined in the context of the present invention; or    -   R⁷ and R⁸, taken together with the nitrogen atom to which they        are bonded, form a heterocycle optionally substituted by one or        more hydroxyl groups, one or more alkyl groups, one or more        alkoxy groups, one or more halogen atoms chosen from fluorine,        chlorine, bromine and iodine atoms, one or more nitro (—NO₂)        groups, one or more nitrile (—CN) groups or one or more aryl        groups, with the alkyl, alkoxy and aryl groups as defined in the        context of the present invention.

According to an alternative form of the invention, the R¹, R² and R³groups of the urea of formula (II) represent, independently of oneanother, a hydrogen atom, a linear or branched C₁-C₇ alkyl group, aC₅-C₆ heterocycle, an aryl group chosen from phenyl or benzyl or aheteroaryl group chosen from imidazolyl or benzimidazolyl, said alkyl,heterocyclic, aryl or heteroaryl groups optionally being substituted byone or more hydroxyl groups, one or more alkyl groups, one or morealkoxy groups, one or more halogen atoms chosen from fluorine, chlorine,bromine and iodine atoms, one or more nitro (—NO₂) groups, one or morenitrile (—CN) groups or one or more aryl groups, with the alkyl, alkoxyand aryl groups as defined in the context of the present invention.

According to a preferred embodiment of the invention, in the silanecompound of formula (III):

-   -   n=1 and Y represents a single bond, and    -   R⁴, R⁵ and R⁶ represent, independently of one another, a        hydrogen atom, an alkyl, aryl or alkoxy group or a silyl or        siloxy group, said alkyl, aryl, alkoxy, silyl and siloxy groups        optionally being substituted, and, preferably, R⁴, R⁵ and R⁶        represent, independently of one another:        -   a hydrogen atom,        -   a linear or branched C₁-C₇ alkyl group,        -   an aryl group chosen from phenyl or benzyl,        -   a linear or branched C₁-C₇ alkoxy group,        -   a silyl group of formula —Si(X)₃ in which each X group,            independently of one another, is chosen from a hydrogen or            halogen atom, or an alkyl or alkoxy group,        -   a siloxy group of formula —O—Si(X)₃ in which each X group,            independently of one another, is chosen from a hydrogen or            halogen atom, or an alkyl or alkoxy group.

Preferably, when the silane compound of formula (III) is a silanecompound in which n=1, it is chosen, for example, from PhSiH₃, Ph₂SiH₂,(EtO)₃SiH or (CH₃)₂HSiOSiH(CH₃)₂.

According to another preferred embodiment of the invention, in thesilane compound of formula (III):

-   -   n>1, advantageously n varies from 1000 to 5000, and Y is an        oxygen atom, and    -   R⁴ is chosen from a hydrogen atom or a methyl group,    -   R⁵ represents a silyl group of formula —Si(X)₃ in which each X        group, independently of one another, is chosen from a hydrogen        or halogen atom, or an alkyl or alkoxy group,    -   R⁶ represents a siloxy group of formula —O—Si(X)₃ in which each        X group, independently of one another, is chosen from a hydrogen        or halogen atom, or an alkyl or alkoxy group.

Preferably, when the silane compound of formula (III) is a polymericorganosilane (n>1), the latter can, for example, bepolymethylhydrosiloxane (PMHS).

When the silane compound of formula (III) is a polymeric organosilane,the number of equivalents introduced into the reaction medium is givenwith respect to the number of hydrides introduced and consequently tothe number of monomers introduced, with respect to the urea of formula(II).

Catalyst, within the meaning of the invention, is understood to mean anycompound which is capable of modifying, in particular by increasing, therate of the chemical reaction in which it participates and which isregenerated at the end of the reaction. This definition encompasses bothcatalysts, that is to say compounds which exert their catalytic activitywithout having to be subjected to any modification or conversion, andcompounds (also known as precatalysts) which are introduced into thereaction medium and which are converted therein into a catalyst.

The catalysts can be chosen from organic catalysts or metal catalysts,the metal catalysts being chosen from metal salts or metal complexes.Organic catalysts exhibit the advantage of making it possible to escapethe problems of toxicity generally observed for metal catalysts and alsothe problems of costs associated with the use of precious metals. In theprocess of the invention, the catalyst is preferably a metal salt usedin the presence or absence of a ligand.

The organic catalysts are generally organic bases chosen from:

-   -   nitrogenous bases, such as, for example, secondary or tertiary        amines chosen from triazabicyclodecene (TBD),        N-methyltriazabicyclodecene (MeTBD),        1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), trimethylamine,        triethylamine, piperidine, 4-dimethylaminopyridine (DMAP),        1,4-diazabicyclo[2.2.2]octane (DABCO), proline, phenylalanine, a        thiazolium salt or N-diisopropylethylamine (DIPEA or DIEA); or    -   phosphorus-based bases, such as, for example, alkyl- and        arylphosphines chosen from triphenylphosphine,        2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) or        triisopropylphosphine; alkyl- and arylphosphonates chosen from        diphenyl phosphate, triphenyl phosphate (TPP),        tri(isopropylphenyl)phosphate (TIPP), cresyl diphenyl phosphate        (CDP) or tricresyl phosphate (TCP); or alkyl and aryl phosphates        chosen from di(n-butyl)phosphate (DBP),        tris(2-ethylhexyl)phosphate or triethyl phosphate;    -   carbon-based bases for which the protonation takes place on a        carbon atom, such as, for example, an N-heterocyclic carbene,        such as a carbene resulting from an imidazolium salt chosen from        1,3-bis(2,6-diisopropylphenyl)-1H-imidazol-3-ium,        1,3-bis(2,6-diisopropylphenyl)-4,5-dihydro-1H-imidazol-3-ium,        1,3-bis(2,4,6-trimethylphenyl)-1H-imidazol-3-ium,        1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydro-1H-imidazol-3-ium,        4,5-dichloro-1,3-bis(2,6-diisopropylphenyl)-1H-imidazol-3-ium,        1,3-di(tert-butyl)-1H-imidazol-3-ium or        1,3-di(tert-butyl)-4,5-dihydro-1H-imidazol-3-ium salts, said        salts being, for example, in the form of chloride salts, as        represented below:

or

-   -   oxygen-based bases, such as, for example, hydrogen peroxide,        benzoyl peroxide or an alkoxide chosen from sodium or potassium        methoxide, ethoxide, propoxide, butoxide, pentoxide or hexoxide.

According to a preferred alternative form of the invention, the organiccatalyst is chosen from triazabicyclodecene (TBD),N-methyltriazabicyclodecene (MeTBD) or1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

When the catalyst is a metal catalyst, it can be chosen from the saltsor complexes of:

-   -   metals chosen from boron, silicon, aluminum, gallium, tin or        indium;    -   alkali metals chosen from sodium and potassium;    -   alkaline earth metals chosen from magnesium and calcium;    -   transition metals chosen from nickel, iron, cobalt, zinc,        copper, rhodium, ruthenium, platinum, palladium or iridium;    -   rare earth metals chosen from lanthanum, cerium, praseodymium or        neodymium.

Preferably, the metal catalyst is a salt or complex of a transitionmetal chosen from nickel, iron, cobalt, zinc, copper, rhodium,ruthenium, platinum, palladium or iridium, or more preferably still fromiron, zinc, copper or ruthenium.

By way of examples, the metal catalyst can be chosen from the followingsalts or complexes:

-   -   Al(OiPr)₃, SnCl₂ or InBr₃, as metal salts or complexes;    -   Na₂CO₃, K₂CO₃ or Cs₂CO₃, as salts or complexes of alkali metals;    -   MgSO₄ or Ca(BH₄)₂, as salts or complexes of alkaline earth        metals;    -   Fe(BH₄)₂.6H₂O, Fe(BF₄)₂.6H₂O, Fe(acac)₃, CuCl, Cu(OAc)₂(H₂O),        Zn(OAc)₂, Zn(BDI)Et or ZnEt₂, as salts or complexes of        transition metals;    -   La(OTf)₃ or CeCl₃, as salts or complexes of rare earth metals.

Metal complex is understood to mean an organometallic or inorganiccoordination compound in which a metal ion is bonded to an organic orinorganic ligand. An organometallic or inorganic complex can be obtainedby mixing a metal salt with a ligand, the latter bonding to the metalvia phosphorus, carbon, nitrogen, oxygen, hydrogen or silicon atoms, forexample. Mention may be made, as organic or inorganic ligand, by way ofindication, of a ligand of the phosphine or amine type, such as, forexample, tris[2-(diphenylphosphino)ethyl]phosphine (PP₃),tricyclohexylphosphine, acetate (AcO), acetylacetonate (acac),1,2-bis(diphenylphosphino)ethane (dppe),N,N,N′,N′-tetramethylethylenediamine (TMEDA),N,N′-bis(2,6-diisopropylphenyl)-β-diketiminate (BDI),1,2-bis(diphenylphosphino)benzene (dppb) or pyridine.

According to a preferred alternative form of the invention, the metalcatalyst is:

-   -   a mixture of an iron metal salt, such as, for example,        Fe(acac)₃, Fe(acac)₂ or Fe(BF₄)₂.6H₂O, with a ligand of        phosphine or amine type, such as, for example TMEDA, dppe or        PP₃; or    -   a mixture of a Cu(OAc)₂.H₂O or Cu(acac)₂ copper salt with a        ligand of phosphine or amine type chosen from TMEDA, dppe or        dpp; or    -   a Zn(Et)₂ zinc salt; or    -   a mixture of an RuCl₂(DMSO)₄ ruthenium salt with a ligand of        phosphine type chosen from PP₃ or dpp.

Some of the abbreviations used for the ligands are represented below:

The catalysts can, if appropriate, be immobilized on heterogeneoussupports in order to ensure ready separation of said catalyst and/or therecycling thereof. Said heterogeneous supports can be chosen fromsupports based on silica gel or on plastic polymers, such as, forexample, polystyrene, carbon-based supports chosen from carbonnanotubes, silicon carbide, alumina or magnesium chloride (MgCl₂).

In the process according to the invention, the reaction temperature canbe between 20 and 150° C., and preferably between 75 and 125° C.

The reaction can be carried out for a period of time ranging from 1 to72 hours, and preferably from 1 to 48 hours.

The process of the invention, in particular the reaction between thedifferent reactants, can take place in one or more solvents chosen from:

-   -   ethers, preferably diethyl ether or THF;    -   hydrocarbons, preferably benzene or toluene;    -   nitrogenous solvents, preferably pyridine or acetonitrile;    -   sulfoxides, preferably dimethyl sulfoxide;    -   alkyl halides, preferably chloroform or methylene chloride.

The molar ratio of the urea of formula (II) to the silane compound offormula (III) is from 0.5 to 5, and preferably from 1 to 3.

The amount of catalyst is from 0.001 to 1 molar equivalent, andpreferably from 0.001 to 1 molar equivalent, with respect to the urea offormula (II).

The different reactants used in the process of the invention (the ureasof formula (II), the silane compounds of formula (III), the catalysts,and the like) are generally commercial compounds or compounds which canbe prepared by any process known to a person skilled in the art.

Another subject matter of the invention is a process for the preparationof insecticides, pesticides, fungicides, pharmaceutical products andcatalysts comprising a stage of preparation of formamidines of formula(I) according to the process of the invention.

In addition to the preceding provisions, the invention also comprisesother provisions which will emerge from the remainder of the descriptionwhich follows, which relates to examples of the synthesis offormamidines of formula (I) according to the process of the invention.

EXAMPLES

The hydrosilylation reaction of the ureas of formula (II) to giveformamidines of formula (I) is carried out according to the followingexperimental protocol.

The urea of formula (I) (1 equivalent), the catalyst (from 0.001 to 1equivalent), the silane (1 to 3 equivalents) and the solvent areintroduced, under an inert atmosphere, in a glove box, into a Schlenktube which is subsequently sealed by a J. Young® tap. The concentrationof urea and of silane in the reaction mixture is approximately 0.5mol·l⁻¹ (concentration calculated on the basis of the volume of solventintroduced). The Schlenk tube is subsequently heated at a temperature of100° C. until the urea has completely converted (reaction for 24 hours).Once the reaction is complete, the mixture is acidified with a 1Naqueous hydrochloric acid solution and the aqueous phase is washed 3times with ether. Potassium hydroxide pellets are subsequently added tothe aqueous phase up to basic pH and then extraction is carried out 3times with ethyl acetate. After drying the organic phase over anhydrousmagnesium sulfate, the ethyl acetate is evaporated under reducedpressure and the pure formamidine is obtained in the form of a whitesolid. In the event of the presence of other organic by-products, theformamidine can be purified by chromatography on silica gel. The use ofa dichloromethane/methanol mixture as eluant makes it possible to obtainthe analytically pure formamidine.

The reaction scheme is as follows:

Two different sources of reducing agents were used: phenylsilane andpolymethylhydrosiloxane (PMHS). In the case of the PMHS, as the silaneis a polymer, the number of equivalents introduced is given with respectto the number of hydrides introduced and thus to the number of monomersintroduced, with respect to the urea. Thus, the introduction of 3equivalents of PMHS corresponds to the introduction of 3 equivalents ofhydride and thus 3 equivalents of PMHS monomers, with respect to theurea.

Different catalysts were tested for the reaction.

A set of results is presented in the following table 1:

TABLE 1 Silane of Yield Urea of formula (II) formula (III) CatalystSolvent T (° C.) %

PhSiH₃ (1 eq.) Fe(BF₄)•6H₂O (5.0 mol %) + PP₃ (5.0 mol %) THF 100° C.91%

PhSiH₃ (1 eq.) Fe(acac)₂ (5.0 mol %) + PP₃ (5.0 mol %) THF 100° C. 98%

PhSiH₃ (1 eq.) Fe(acac)₂ (5.0 mol %) + dppb (5.0 mol %) THF 100° C. 34%

PMHS (3 eq.) Cu(OAc)₂•H₂O (5.0 mol %) + dppb (7.5 mol %) THF 100° C. 30%

Ph₂SiH₂ (1 eq.) Cu(OAc)₂•H₂O (10.0 mol %) + dppb (15 mol %) THF 100° C.32%

(EtO)₃SiH (1 eq.) Cu(OAc)₂•H₂O (10.0 mol %) + dppb (15 mol %) THF 100°C. 83%

TMDS (6 eq.) Cu(OAc)₂•H₂O (10.0 mol %) + dppb (15 mol %) THF 100° C. 30%

PhSiH₃ (1 eq.) Zn(Et)₂ (5.0 mol %) THF 100° C. 35%

PhSiH₃ (1 eq.) Fe(acac)₂ (5.0 mol %) + PP₃ (5.0 mol %) THF 100° C. 39%

PhSiH₃ (1 eq.) Fe(acac)₂ (5.0 mol %) + PP₃ (5.0 mol %) THF 100° C. 64%

PhSiH₃ (1 eq.) Fe(acac)₂ (5.0 mol %) + PP₃ (5.0 mol %) THF 100° C. 31%

PhSiH₃ (1 eq.) Fe(acac)₂ (5.0 mol %) + PP₃ (5.0 mol %) THF 100° C. 81%

PhSiH₃ (1 eq.) Fe(acac)₂ (5.0 mol %) + PP₃ (5.0 mol %) THF 100° C. 56%

PhSiH₃ (1 eq.) Fe(acac)₂ (5.0 mol %) + PP₃ (5.0 mol %) THF 100° C. 61%

PhSiH₃ (1 eq.) Fe(acac)₂ (10.0 mol %) + PP₃ (10.0 mol %) THF 100° C. 65%

PhSiH₃ (1 eq.) Fe(acac)₂ (5.0 mol %) + PP₃ (5.0 mol %) THF 100° C. 74%

PhSiH₃ (1 eq.) Fe(acac)₂ (5.0 mol %) + PP₃ (5.0 mol %) THF 100° C. 46%

PhSiH₃ (1 eq.) Fe(acac)₂ (5.0 mol %) + PP₃ (5.0 mol %) THF 100° C. 46%

PhSiH₃ (1 eq.) Fe(acac)₂ (5.0 mol %) + PP₃ (5.0 mol %) THF 100° C. 63%

PhSiH₃ (1 eq.) Fe(acac)₂ (5.0 mol %) + PP₃ (5.0 mol %) THF 100° C. 40%

PhSiH₃ (1 eq.) Fe(BF₄)•6H₂O (5.0 mol %) + PP₃ (10.0 mol %) THF 100° C.35%

PhSiH₃ (2 eq.) RuCl₂(DMSO)₄ (5.0 mol %) THF 100° C. 45%

PhSiH₃ (2 eq.) RuCl₂(DMSO)₄ (5.0 mol %) THF 100° C. 62%

PhSiH₃ (2 eq.) RuCl₂(DMSO)₄ (5.0 mol %) + dppb (5.0 mol %) THF 100° C.68%

PhSiH₃ (2 eq.) RuCl₂(DMSO)₄ (5.0 mol %) + PP₃ (5.0 mol %) THF 100° C.65%

(CH₃)₂SiHO- SiH(CH₃)₂ (6 eq.) RuCl₂(DMSO)₄ (10.0 mol %) THF 100° C. 31%

PhSiH₃ (2 eq.) RuCl₂(DMSO)₄ (5.0 mol %) THF 100° C. 51%

1. A process for the preparation of formamidines of formula (I):

in which: R¹, R² and R³ represent, independently of one another, ahydrogen atom, an alkyl, alkenyl, alkynyl, aryl or heteroaryl group, aheterocycle or a silyl, siloxy or amino group, said alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocycle, silyl, siloxy and amino groupsoptionally being substituted, or R¹ and R², taken together with thenitrogen atom to which they are bonded, form an optionally substitutedheterocycle, or R¹ and R³, taken together with the nitrogen atom towhich they are bonded, form an optionally substituted heterocycle,wherein a urea of formula (II), in which R¹, R² and R³ are as definedabove:

is reacted, in the presence of a catalyst, with a silane compound offormula (III):

in which n is an integer varying from 1 to 20 000, and when n=1 and Yrepresents a single bond, and R⁴, R⁵ and R⁶ represent, independently ofone another, a hydrogen or halogen atom, a hydroxyl, alkyl, alkenyl,alkynyl, aryl or alkoxy group or a silyl, siloxy or amino group, saidalkyl, alkenyl, alkynyl, aryl, alkoxy, silyl, siloxy and amino groupsoptionally being substituted, or R⁶ is as defined above and R⁴ and R⁵,taken together with the silicon atom to which they are bonded, form anoptionally substituted silylated heterocycle, or when n>1, Y is anoxygen atom, and R⁴ represents a hydrogen or a halogen atom or an alkylor alkoxy group, R⁵ represents a silyl group of formula —Si(X)₃ in whicheach X group, independently of one another, is chosen from a hydrogen orhalogen atom or an alkyl or alkoxy group, R⁶ represents a siloxy groupof formula —O—Si(X)₃ in which each X group, independently of oneanother, is chosen from a hydrogen or halogen atom, or an alkyl oralkoxy group.
 2. The process as claimed in claim 1, wherein the urea offormula (II), R¹, R² and R³ represent, independently of one another, ahydrogen atom, a linear or branched C₁-C₇ alkyl group, a C₅-C₆heterocycle, an aryl group chosen from phenyl or benzyl or a heteroarylgroup chosen from imidazolyl or benzimidazolyl, said alkyl,heterocyclic, aryl or heteroaryl groups optionally being substituted. 3.The process as claimed in claim 1, wherein the silane compound offormula (III): n=1 and Y represents a single bond, and R⁴, R⁵ and R⁶represent, independently of one another, a hydrogen atom, an alkyl, arylor alkoxy group or a silyl or siloxy group, said alkyl, aryl, alkoxy,silyl and siloxy groups optionally being substituted.
 4. The process asclaimed in claim 3, wherein the silane compound of formula (III), R⁴, R⁵and R⁶ represent, independently of one another: a hydrogen atom, alinear or branched C₁-C₇ alkyl group, an aryl group chosen from phenylor benzyl, a linear or branched C₁-C₇ alkoxy group, a silyl group offormula —Si(X)₃ in which each X group, independently of one another, ischosen from a hydrogen or halogen atom, or an alkyl or alkoxy group, asiloxy group of formula —O—Si(X)₃ in which each X group, independentlyof one another, is chosen from a hydrogen or halogen atom, or an alkylor alkoxy group.
 5. The process as claimed in claim 1, wherein thesilane compound of formula (III): n>1 and Y is an oxygen atom, and R⁴ ischosen from a hydrogen atom or a methyl group, R⁵ represents a silylgroup of formula —Si(X)₃ in which each X group, independently of oneanother, is chosen from a hydrogen or halogen atom, or an alkyl oralkoxy group, R⁶ represents a siloxy group of formula —O—Si(X)₃ in whicheach X group, independently of one another, is chosen from a hydrogen orhalogen atom, or an alkyl or alkoxy group.
 6. The process as claimed inclaim 5, wherein the silane compound of formula (III), n varies from1000 to
 5000. 7. The process as claimed in claim 1, wherein the catalystis chosen from organic catalysts or metal catalysts, the metal catalystsbeing chosen from metal salts or metal complexes.
 8. The process asclaimed in claim 7, wherein the organic catalyst is: a secondary ortertiary amine chosen from triazabicyclodecene (TBD),N-methyltriazabicyclodecene (MeTBD), 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU), trimethylamine, triethylamine, piperidine,4-dimethylaminopyridine (DMAP), 1,4-diazabicyclo[2.2.2]octane (DABCO),proline, phenylalanine, a thiazolium salt or N-diisopropylethylamine(DIPEA or DIEA); or an alkyl- or arylphosphine chosen fromtriphenylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP)or triisopropylphosphine; an alkyl- or arylphosphonate chosen fromdiphenyl phosphate, triphenyl phosphate (TPP),tri(isopropylphenyl)phosphate (TIPP), cresyl diphenyl phosphate (CDP) ortricresyl phosphate (TCP); or an alkyl or aryl phosphate chosen fromdi(n-butyl)phosphate (DBP), tris(2-ethylhexyl)phosphate or triethylphosphate; or an N-heterocyclic carbene, such as a carbene resultingfrom an imidazolium salt chosen from1,3-bis(2,6-diisopropylphenyl)-1H-imidazol-3-ium,1,3-bis(2,6-diisopropylphenyl)-4,5-dihydro-1H-imidazol-3-ium,1,3-bis(2,4,6-trimethylphenyl)-1H-imidazol-3-ium,1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydro-1H-imidazol-3-ium,4,5-dichloro-1,3-bis(2,6-diisopropylphenyl)-1H-imidazol-3-ium,1,3-di(tert-butyl)-1H-imidazol-3-ium or1,3-di(tert-butyl)-4,5-dihydro-1H-imidazol-3-ium salts, said salts beingin the form of chloride salts, an oxygen-based base chosen from hydrogenperoxide, benzoyl peroxide or an alkoxide chosen from sodium orpotassium methoxide, ethoxide, propoxide, butoxide, pentoxide orhexoxide.
 9. The process as claimed in claim 8, wherein the organiccatalyst is chosen from triazabicyclodecene (TBD),N-methyltriazabicyclodecene (MeTBD) or1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
 10. The process as claimed inclaim 7, wherein the metal catalyst is chosen from the salts orcomplexes of: metals chosen from boron, silicon, aluminum, gallium, tinor indium; alkali metals chosen from sodium and potassium; alkalineearth metals chosen from magnesium and calcium; transition metals chosenfrom nickel, iron, cobalt, zinc, copper, rhodium, ruthenium, platinum,palladium or iridium; rare earth metals chosen from lanthanum, cerium,praseodymium or neodymium.
 11. The process as claimed in claim 10,wherein the metal catalyst is a salt or complex of a transition metalchosen from nickel, iron, cobalt, zinc, copper, rhodium, ruthenium,platinum, palladium or iridium.
 12. The process as claimed in claim 11,wherein the metal catalyst is: a mixture of an Fe(acac)₃, Fe(acac)₂ orFe(BF₄)₂.6H₂O iron salt with a ligand of phosphine or amine type chosenfrom TMEDA, dppe or PP₃; or a mixture of a Cu(OAc)₂.H₂O or Cu(acac)₂copper salt with a ligand of phosphine or amine type chosen from TMEDA,dppe or dpp; or a Zn(Et)₂ zinc salt; or a mixture of an RuCl₂(DMSO)₄ruthenium salt with a ligand of phosphine type chosen from PP₃ or dpp.13. The process as claimed in claim 1, wherein the reaction is at atemperature of between 50 and 150° C.
 14. The process as claimed inclaim 1, wherein the reaction is carried out for a period of time of 1to 72 hours.
 15. The process as claimed in claim 1, wherein the molarratio of the urea of formula (II) to the silane compound of formula(III) is from 0.5 to
 5. 16. The process as claimed in claim 1, whereinthe amount of catalyst is from 0.001 to 1 molar equivalent with respectto the urea of formula (II).
 17. A process for the preparation ofinsecticides, pesticides, fungicides, pharmaceutical products andcatalysts comprising a stage of preparation of formamidines of formula(I) as claimed in claim
 1. 18. The process as claimed in claim 1,wherein the reaction is at a temperature of between 75 and 125° C. 19.The process as claimed in claim 1, wherein the reaction is carried outfor a period of time of 1 to 48 hours.
 20. The process as claimed inclaim 1, wherein the molar ratio of the urea of formula (II) to thesilane compound of formula (III) is from 1 to 3.